A Career Dedicated to Helping Hearts

When UC San Diego’s Dr. Daniel Steinberg began devoting his life to lipoproteins, it was a different world.

Fried food and red meat ruled the postwar family dinner table. Blood-cholesterol levels didn’t come up in conversation at the beauty shop. And fats were the low man on the medical-research totem pole--interesting, but hardly the equal of proteins or nucleic acids.

Four decades later, largely because of his early leadership, millions of Americans worry about how much cholesterol is flowing in their veins. Even the cholesterol treatment guidelines their doctors use were developed by a federal panel Steinberg chaired.

And, because of Steinberg’s current work, five or 10 years from now we may be taking drugs that stop the cascade of chemical reactions necessary for fat-filled cells to plug arteries and cause heart attack and stroke.

“Dan Steinberg brought to (atherosclerosis research) a type of scientific distinction that gave the field immediate credibility,” said Dr. Michael S. Brown, the Texas researcher who with Dr. Joseph L. Goldstein in 1985 won a Nobel Prize for their work with lipoproteins.

“And the work he’s doing now is truly amazing--equally as exciting as anything he’s ever done in the past,” Brown said. “It’s something every scientist dreams of, to be productive for a long period throughout life.”

To be held in seemingly universal high esteem is Steinberg’s reward for a career as an original thinker who demands rigorous scientific proof for new ideas--even his own.

Steinberg was surprised recently when, looking at some of his more than 400 scientific papers, he found that it wasn’t until 1970 that he accepted that lowering all Americans’ high cholesterol levels would reduce their risk of heart attack.

“Proof is a relative thing. There are degrees of proof and there are degrees of conviction,” Steinberg explains about that long time line.

So, though the cholesterol-atherosclerosis link wasn’t proved well enough for Steinberg the scientist until 1970, the connection was good enough for Steinberg the father a decade earlier.

As fast food was gaining its place in the American diet in the early 1960s, menus at the Steinberg household looked like nouvelle cuisine , says his 34-year-old daughter, Anne Margolis, now a lawyer in the San Francisco Bay Area.

“Our family was always interested in eating light,” Margolis recalls, in words that come at the same thoughtful pace that distinguishes her father’s speech.

“We always tended to eat grilled meat instead of fried meat and a lot of chicken, fish and vegetables. But I never felt deprived.”

Not so, however, in 1962, when Steinberg and wife, Sara, switched their three young children to low-fat milk.

“First we served them skim milk, and they said, ‘Bleah, this is like blue water.’ And they wouldn’t drink it,” Steinberg said. “So, after they went to bed, we would take the regular milk and spike it with one-quarter skim milk in the same bottle. It was really a very dirty trick--but they didn’t notice a thing.

“And after a couple of weeks, we diluted it 50-50 skim and whole milk, and they didn’t say a thing. And then we gradually worked it down. Later, if they got whole milk, they’d say, ‘Ick, this is creamy. We don’t like this.’ ”

Steinberg’s home base at UCSD is an office in one corner of the Basic Science Building, a place whose halls are filled with refrigerators, warning signs and other markers of the research going on there. As he talks, a lab associate stops by to consult over which pictures to use in their next publication.

“I’m not sitting at a desk far removed from the lab. I’m talking data with everybody every day, and planning experiments,” Steinberg said.

Each sentence is slowly and thoughtfully delivered--remarkably free of self-interruptions, convoluted phrasings and unfinished thoughts. Every fifth word or so is slightly emphasized, as though verbally italicized.

“The most fun is generating ideas,” he said. “The light bulb is where it’s at. The fun and excitement of science is creation. I’m very much involved in that, and that’s what gives me the greatest pleasure.”

After studying at Harvard University, Steinberg came to the National Heart Institute in 1950 to join his thesis adviser, Dr. Christian B. Anfinsen, in setting up the institute.

The move also had the advantage of enlisting him in the Public Health Service, keeping him out of the draft during the Korean War.

“Some might consider that a little bit shabby, but I don’t consider it shabby at all,” Steinberg said. “I had done my duty. I was in the Army (in World War II), but I hadn’t quite finished two years. And the rule was that, if you hadn’t finished 24 months, you were eligible for re-draft.

“So I took a commission in the U.S. Public Health Service at the (National Institutes of Health), and it turned out great for me. It was the best years of my life.”

Because Anfinsen was more interested in protein structure--a field in which he won a Nobel Prize in 1972--it fell to Steinberg to pursue hints that fat-protein combinations called lipoproteins were important in human metabolism.

“I was just having a ball. Remember, in those days the NIH was expanding at an enormous rate. Money flowed like water. You could get whatever the hell you wanted,” Steinberg said.

The field was the equivalent of what molecular biology has been in medicine over the last decade.

“Oh, such excitement! Every day something new would come up, because it was a totally virginal field,” he said. “We didn’t even know what the proteins were in lipoproteins.

“So everything you did was new. It was tremendous. We were the first ones to show that, if you took liver slices and incubate them, you can show that they put out lipoproteins into the medium.”

As with so much of Steinberg’s work, this conclusion--that the liver is the source of lipoproteins in the blood--is textbook knowledge today.

The lipid research group he headed also served as a launching pad for young medical researchers, who later joined him to become leaders in the U.S. atherosclerosis research infrastructure.

These include Richard Havel at UC San Francisco; DeWitt S. Goodman at Columbia University; Howard Eder at Albert Einstein College of Medicine and Donald S. Fredrickson, who went on to head the National Institutes of Health from 1975 to 1981.

Steinberg left the NIH in 1968 to move to the newly established UCSD medical school.

He says he chose San Diego over UC San Francisco because he was offered a role here in setting medical school policies, even though he wasn’t a department head.

“He was an exemplar of what one would want in a person to start up a new medical school,” said Dr. Clifford Grobstein, now retired as UCSD medical dean. “He had considerable interest in students and new forms of medical education, but also hoped to establish a strong research center.”

Steinberg’s status has earned him one of the top five faculty salaries at UCSD: $190,000, according to university records. Of that, $110,000 is paid by the university, and the rest comes from research grants.

Steinberg is considered responsible for bringing one of seven federal Lipid Research Clinics to UCSD, and with it federal grants that he says have averaged about $2 million a year since 1971.

Indeed, it was Steinberg’s position as the well-paid guru of federally funded cholesterol research that made him an implied target last fall.

In an article in The Atlantic Monthly, writer Thomas J. Moore contended that there was no firm scientific basis for doctors to act aggressively to reduce cholesterol levels in their patients.

He suggested that the experts behind federal cholesterol treatment guidelines--which Steinberg helped develop--had gained much research money by glossing over their own failure to prove a case against excess cholesterol.

The accusations stung, and Steinberg responded quickly with a restrained and scholarly letter. But, in an earlier version, his feelings emerged more strongly:

“The tone of the Moore article is the tone of yellow journalism, more appropriate to the National Enquirer than to The Atlantic Monthly,” Steinberg wrote. “There are phrases sprinkled liberally about that imply double-dealing and conspiracy. Mr. Moore’s fishing in the wrong pond. Are the Girl Scouts of America next?”

At UCSD, Steinberg takes credit for establishing here in 1981 one of the first colonies in this country of Watanabe rabbits--a variety from Japan that has extremely high blood cholesterol levels of 600 to 700 milligrams no matter what it is fed. (In humans, anything above 230 milligrams per deciliter of blood serum is considered high.)

Not only do these rabbits naturally show atherosclerosis, but the lipid content of their blood is very similar to that seen in humans.

A friend told Steinberg about the rabbits after hearing Yoshio Watanabe of Kobe University in Japan describe them at a meeting in Italy.

“I could see immediately that they were extremely valuable,” Steinberg said. “I immediately wrote to Watanabe, and he wrote back and said, yes, he would be glad to send me a breeding pair if I signed an agreement that any papers that were published during the first year or two using his rabbits would bear his name as a co-author, and that I would promise not to give those rabbits to anybody else.

“Now, that was a very unusual request. In the United States people would never do that. They’d just let you have some of their rabbits. But I signed because I wanted those rabbits.

“I got four rabbits from him,” Steinberg recalls. “I think the air fare was something like $400 each--and they were well worth it.”

UCSD’s colony of about 100 rabbits now being expanded because of upcoming experiments--continues to offer the earliest hints at answers about how atherosclerosis occurs in humans.

The latest work with the rabbits in Steinberg’s lab has been about the role that oxidation of low-density lipoprotein (LDL) plays in atherosclerosis. The emerging picture of this process that precedes heart attack and stroke looks like this:

In the presence of high levels of lipoproteins, which are loosely labeled as cholesterol, white blood cells called monocytes begin sticking to artery walls.

They eventually work their way into the wall and, using a receptor in the cell wall, they begin gobbling up LDL, the “bad” cholesterol molecule. This turns them into fat-filled “foam cells” that form fatty streaks inside arteries and eventually atherosclerotic plaques.

When these plaques narrow the artery so much that they affect heart function, they can cause a heart attack. Blockage in arteries leading to the brain leads to stroke.

What the Steinberg lab’s recent work has shown is that the monocytes gobble up cholesterol three to 10 times faster if it has been chemically oxidized. An enzyme called lipoxygenase appears to be involved.

“It’s an enzyme that acts on fatty acids and introduces molecular oxygen into the fatty acid,” Steinberg said. “When that (modified fatty acid) gets into the LDL under the right conditions it causes a chain reaction, a big explosive amplification so that a lot of other fatty acids in the LDL molecule get oxidized.”

Steinberg and others believe that using drugs to block the oxidation could prove a key strategy in slowing atherosclerosis. There is preliminary evidence for this in a rabbit experiment conducted in Japan, he says.

But Steinberg is exercising his characteristic scientific caution and all his considerable influence to try to slow down a push for clinical trials of antioxidant drugs against atherosclerosis.

One of the antioxidants being touted is Vitamin E. But, when supplements are given .it is largely stored in the liver, not released into the blood where it could block the LDL oxidation, Steinberg points out.

“Some people are pushing me like crazy to go on record that we should go out and do a clinical trial and blah and blah--and I’m just totally resisting until we have sufficient additional animal evidence,” he said.

There are pragmatic reasons as well as scientific ones for holding off, he said.

“If you do the wrong study, with the wrong antioxidant and get a negative result, it’ll be very difficult to get a second try, to get a second chance,” he said. “So I’m really anxious that we don’t jump the gun.”

Steinberg’s honors over the years have included election to the National Academy of Sciences and awards from the American Heart Assn., the National Cholesterol Education Program and many other groups.

But Steinberg calls himself an “also-ran” for the Nobel Prize that went to Brown and Goldstein in 1985. They described the workings of the LDL receptor, setting the stage for all subsequent understanding of the atherosclerotic process in humans.

But he was among the six scientists whose contributions Brown and Goldstein recognized by inviting them to Stockholm for the awards ceremony.

Steinberg’s eyes misted over as he described the grandeur of the event. “Gosh, I was so moved,” he said, his voice cracking. He shook his head and paused a few seconds before adding, “I’ve had such excitement in my life.”

Steinberg is free in his own acknowledgement of those who have co-authored his many scientific papers.

“No individual works in science--unless he’s an Albert Einstein--without any help from anybody. Theoretical physicists can do it. Experimental people can never work without an awful lot of help from collaborators,” he said.

“I was given the research achievement award by the Council on Arteriosclerosis at the annual meeting of the Heart Assn. year before last, and I said, ‘Well, I’m not going to accept this award unless all the people who are here who have ever worked with me stand up and accept it with me.’ I think about 30 people stood up,” he said, his voice cracking again with emotion. “That was very moving.”

Later, a characteristic assurance back in his voice, Steinberg declares: “Anybody who tries to put himself forward as having done it all himself is crazy, or a megalomaniac.”

In his work, as well as his stances on issues such as the antioxidant tests, others in the field say Steinberg is taken seriously because he demands scientific rigor but is open to new ideas.

“I know people like me and trust me, in the sense that I will give a fair and objective evaluation to what they have to say,” Steinberg said. “That’s something I treasure more than anything else: that I have a reputation in my field for honesty and objectivity. And what could be more valuable and more precious?”